A major challenge in the area of the parenteral administration of biologically active materials is the development of a controlled delivery device that is small enough for intravenous application and which has a long circulating half-life. Biologically active materials administered in such a controlled fashion into tissue or blood are expected to exhibit decreased toxic side effects compared to when the materials are injected in the form of a solution, and may reduce degradation of sensitive compounds in the plasma.
A number of injectable drug delivery systems have been investigated, including microcapsules, microparticles, liposomes and emulsions. A significant obstacle to the use of these injectable drug delivery materials is the rapid clearance of the materials from the blood stream by the macrophages of the reticuloendothelial system (RES). For example, polystyrene particles as small as sixty nanometers in diameter are cleared from the blood within two to three minutes. Polystyrene particles are also not biodegradable and therefore not therapeutically useful.
Polymers which are degraded by a physical or chemical process in response to contact with body fluid, while implanted or injected, are generally considered to be biodegradable. Biodegradable polymers have been the subject of increasing interest as materials which can be employed to form a wide variety of pharmaceutical preparations and other biomedical products. Examples of medical applications for biodegradable polymers include tablet coatings, plasma substitutes, gels, contact lenses, surgical implants, as ingredients of eyedrops, and as long-lived circulating and targeted drugs.
However, many polymers have hydrophobic domains and, consequently, their biocompatability is limited. Hydrophobic polymers are vulnerable to non-specific interactions with proteins and lipids which also may cause undesirable side effects. In addition, synthetic polymers, such as vinyl, acrylic and methacrylic polymers, which typically have a hydrophobic main chain, do not degrade readily in vivo.
Hydrophilic polymers are common in nature. For example, polysaccharides are naturally-occurring polymers which include hydrolytically-sensitive acetals in their main chain. However, polysaccharides can interact with cell receptors and/or plasma opsonins, and can cause adverse reactions and other non-desirable effects.
In addition, the activity and half-life of biological agents, such as ecto-enzymes, which are introduced into the blood stream is transient, which therefore limits the biological agents' potential application. To achieve effective therapies, repeated large enzyme dosing may be required. This may in turn result in increased toxicity and side effects as an immune response to the extended enzyme introduction.
Therefore, a need exists for a polymer system which overcomes or minimizes the above-referenced problems and is amenable to modification by a biologically active agent wherein the agent is stabilized and released in a timed manner.